About the Authors
C. Benjamin Lai, and Eric Coomes are medical students at the University
of Toronto, Toronto, ON. Molly Whalen-Browne is a medical student at
McMaster University, Hamilton, ON. Christian Kraeker is with the Department of
Internal Medicine, McMaster University, Juravinski Hospital and Cancer
Centre, Hamilton, ON.
Correspondence may be directed to: kraeker@mcmaster.ca

Abstract

Typhoid fever is a rare disease in North America. We present the case of a
21-year-old female who developed invasive Salmonella typhi
infection after returning from rural Pakistan. The patient presented with
classic signs of enteric infection including high fever, diarrhea, and a
tongue coated in white patches. The patient developed hematologic
complications of anemia and splenic infarction. Investigations, imaging
studies and treatment are discussed. The case outlines both common and
uncommon complications of typhoid fever and reminds the clinician of its
importance in the differential of fever in the returning traveller. Four
key point to consider are:

1. Fever in a returning traveler has a broad differential diagnosis, but
concurrent abdominal symptoms should result in blood cultures to assess for
gram-negative bacteria. 2. Ceftriaxone, azithromycin, or fluoroquinolones
are the treatments of choice for Salmonella typhi, although
clinicians should be aware of increasing resistance to the latter and base
treatment on sensitivity testing. 3. Anemia during typhoid fever can be
multifactorial and include elements of gastrointestinal blood loss,
hemolysis and transient marrow suppression. 4. Spleen involvement can lead
to complications such as splenic infarction or abscess formation.

The patient was a 21-year-old female who had visited friends and relatives
in rural Pakistan. She had received standard childhood immunizations, but
did not seek any specific travel vaccinations or advice. She was previously
otherwise healthy. During her trip, she was exposed to numerous infectious
risk factors including eating street food, drinking unpasteurized milk,
contact with farm animals, wooded areas, and freshwater lakes. She was not
exposed to animal bites, IV drug use, nor sexual activity while abroad. She
first became ill 19 days into her vacation, experiencing daily bilious
vomiting and fevers as high as 39.5°C. These symptoms subsided for one day
after being given antibiotics of an unknown type by a relative, but
subsequently returned with the additional development of non-bloody
diarrhea. She spent a total of 26 days abroad and presented to the
emergency department 6 days after returning to Canada. Thus, she presented
having been ill for approximately 2 weeks.

At presentation, she had diffuse myalgia, headache, and periumbilical pain.
Her triage vital signs showed a temperature of 38.6°C, a heart rate of 110
beats/min, and a blood pressure of 101/58 mm Hg. The physical examination
was significant for buccal ulcers, a tongue coated in white patches, and
epigastric tenderness. Her investigations showed anemia, mild haemolysis
and abnormal liver enzymes (see Table 1 for abnormal results). An abdominal
ultrasound showed the presence of splenomegaly at 13.7 cm. Her initial
blood cultures grew gram-negative bacilli after 14 hours. This was
subsequently identified to be Salmonella typhi . She was admitted
and empiric ceftriaxone was started.

Over the next 11 days, the patient experienced daily fevers ranging from
38.7 to 40.5°C before defervescing. Salmonella typhi was also
identified in both her urine and feces. The detected Salmonella typhi was sensitive to ampicillin and ciprofloxacin,
and she was stepped down to oral ciprofloxacin once she began to tolerate
an oral diet. The infectious disease service advised treatment for a total
of 3 weeks.

By day 3 of admission, free hemoglobin was no longer evident and her
haptoglobin had normalized. However, her hemoglobin continued to trend
downwards. Initially, there was no reticulocyte response. On day 9, the
patient experienced palpitations and had a hemoglobin of 69 g/L. She was
transfused with one unit of packed red blood cells and her hemoglobin
stabilized for the remainder of the hospitalization. The day before she
showed defervescence and clinical improvement, her reticulocyte count had
increased to 92 × 109/L.

Due to ongoing epigastric pain, the patient had an abdominal computed
tomography (CT) and ultrasound on day 4 of admission. These studies
revealed a 2 cm wedge shaped infarct at the lateral border of the spleen
(Figure 1). Three subsequent ultrasounds during her admission confirmed a
stable splenic infarct.

The patient stayed in hospital for an additional week due to hospital
acquired pneumonia. She was discharged home on day 21.

Figure 1. Computed tomography scan showing the splenic infarct.

Discussion

The clinical presentation of Salmonella typhi is relatively
non-specific, and thus a broad differential must be considered in fever in
a returning traveller. Consideration must be given to both regional
pathogens and exposure to risk factors. The differential here is broad and
includes parasites (malaria, giardia, amoebic abscess), bacteria ( Salmonella typhi, Salmonella paratyphi, enteric gram-negative
bacilli, leptospora, rickettsia, brucella), and viruses (dengue, hepatitis,
human immunodeficiency virus) amongst other organisms.

While there are 22 millioncases of typhoid fever
annually, it is rare in high-income settings with only a few hundred cases
reported annually in Canada and the United States.1

Typhoid fever typically presents with fever and malaise, with a 7–14 day
incubation period after ingestion of the gram-negative bacilli, most
commonly from contaminated food or water. The bacteria penetrate the mucosa
of the small intestine and enter the Peyer’s patches where they are
phagocytosed by macrophages, surviving intracellularly. The
salmonella-infected macrophages subsequently distribute via the lymphatics
to reticuloendothelial tissues such as the liver, spleen, lymph nodes and
bone marrow.2

Although fluroquinolones are the most effective agents for susceptible S.
typhi, increasing rates of resistance have led to the use of third
generation cephalosporins or azithromycin for empiric therapy.
Defervescence usually occurs after approximately one week of therapy. If a
fully susceptible organism is identified, therapy should be stepped down to
ciprofloxacin, as was the case in our patient.1,4,5

The etiology of the anemia was likely multi-factorial, involving
gastrointestinal bleeding, haemolysis, and bone marrow suppression.
Gastrointestinal bleeding can develop from Peyer’s patch necrosis and
occurs in up to 10% of hospitalized patients.1 Intestinal
perforation is a feared complication of typhoid fever which can present
insidiously with worsening anemia and abdominal pain or more classically,
with an acute abdomen. Imaging studies did not reveal frank perforation in
our patient. However, it is conceivable that she was experiencing
clinically silent gastrointestinal bleeding.

The patient's splenomegaly secondary to infection likely contributed an
extravascular haemolytic component. The free hemoglobin and abnormal
haptoglobin pointed to a concurrent intravascular haemolytic event.
However, this was likely mild due to a normal bilirubin. The lactate dehydrogenase elevation could be the result of both mild
haemolysis and acute liver disease. There is in vitro evidence
that Salmonella typhi responds to host neuroendocrine stress
hormones by releasing haemolysin E, which could have contributed to the
patient's haemolytic picture.6

In a small cohort study, G6PD deficiency has been proposed as a risk factor
for haemolysis during typhoid fever.7 The hematological workup
of our patient did not reveal glucose-6-phosphate dehydrogenase (G6PD)
deficiency, autoimmune mediated haemolysis, spherocytosis, or beta
thalassemia. We did not perform an alpha thalassemia genetic test. Thus, it
is still possible that our patient harbours an intrinsic haemoglobinopathy
that predisposed her to haemolysis during Salmonella typhi
infection.

While the patient's anemia worsened during the initial stages of her
hospital admission, her early reticulocyte counts did not respond with an
increase. At least one report of a small cohort of typhoid fever patients
showed that Salmonella typhi can infiltrate the bone marrow and cause
isolated anemia or mixed cytopenias.8 In this report, 28 of 36
patients experienced disturbances in at least one blood cell line. When our
patient's clinical symptoms of fever and diarrhea began to improve, her
reticulocyte count also began to respond. Her Salmonella typhi
infection may have initially caused an element of bone marrow suppression,
negating the expected rise in reticulocytes. From a clinical standpoint,
bone marrow biopsies may be too invasive for the majority of typhoid fever
patients.

Splenic complications are uncommon in typhoid infections. The differential
for the lesion found on our patient's spleen included abscess and
infarction, which have both been previously reported.9,10 In our
patient, a non-evolving infarction was confirmed by multiple imaging
studies. Other causes of splenic infarct including haemoglobinopathy,
hematologic malignancy, embolic disorders and trauma were unlikely in this
patient given the investigations and history of presenting illness.
However, in the absence of genetic testing for alpha thalassemia, we are
unable to rule out the possibility of the splenic infarct arising from an
underlying haemoglobinopathy, as opposed to exclusively from the typhoid
fever. Regardless, this case highlights the importance of monitoring the
spleen for complications in invasive S. typhi infections.

Declaration

The authors declare no competing interests.

No funding was required in the development of this manuscript

All four persons named contributed equally to the development of this
manuscript and qualify as authors.